A safety review of approved intrathecal analgesics for chronic pain management.

Introduction: Intrathecal (IT) drug therapy is an effective treatment option for patients with chronic pain of malignant or nonmalignant origin, with an established safety profile and fewer adverse effects compared to oral or parenteral pain medications. Morphine (a µ-opioid receptor agonist) and ziconotide (a non-opioid calcium channel antagonist) are the only IT agents approved by the U.S. Food and Drug Administration for the treatment of chronic pain. Although both are considered first-line IT therapies, each drug has unique properties and considerations.Areas Covered: This review will evaluate the pivotal trials that established the use of morphine and ziconotide as first-line IT therapy for patients with chronic pain, as well as safety and efficacy data generated from various retrospective and prospective studies.Expert Opinion: Morphine and ziconotide are effective IT therapies for patients with chronic malignant or nonmalignant pain that is refractory to other interventions. IT ziconotide is recommended as a first-line therapy due to its efficacy and avoidance of many adverse effects commonly associated with opioids. The use of IT morphine is also considered first-line; however, the risks of respiratory depression, withdrawal with drug discontinuation or pump malfunction, and the development of tolerance require careful patient selection and management.

[What became of Prialt®? : Observational study on the use of ziconotide in the treatment of chronic pain]. / Was wurde eigentlich aus Prialt®? : Beobachtungsstudie über den Langzeiteinsatz von Ziconotid in der Behandlung chronischer Schmerzen.

BACKGROUND: Prialt® was approved by the European Medicine Agency in February 2005. Besides morphine, it is the only analgesic approved for long-term intrathecal infusion in the treatment of chronic pain. As it does not bind to opioid receptors, its use in the treatment of chronic pain seemed to be safer and to lead to less adverse events compared with morphine. However, it is an orphan drug and studies of its long-term use are rare. QUESTIONS: What role does Prialt® play in the treatment of chronic pain compared with other analgesics given intrathecally? What impact do the initial dose and the rate of infusion have on the analgesic effect and on the incidence of side effects? MATERIAL AND METHODS: Medical reports were used to identify all patients receiving ziconotide monotherapy from February 2005 to the end of the analysis period in October 2018 in our department. Furthermore, a questionnaire was created and given to the patients to find out more about their experience with ziconotide. RESULTS: The study included 12 patients, all of whom suffered from at least one adverse event. The most common adverse events were forgetfulness and paraesthesia, each affecting 25% of the patients. One third of the patients discontinued ziconotide therapy due to severe adverse events. The mean initial dose was 1.98 µg/day. DISCUSSION: Ziconotide was used at the Jena University Hospital according to the latest guidelines. Nevertheless, morphine and other opioid analgesics are still more frequently used in the intrathecal management of chronic pain. There are various reasons for this, but the narrow therapeutic index, the high incidence of adverse events, and the difficulties in finding the right dose are among the most important.

Ziconotide-Induced Oro-lingual Dyskinesia: 3 Cases.

Background: Ziconotide (ZCN), a nonopioid analgesic, is first-line intrathecal therapy for patients with severe chronic pain refractory to other management options. We describe three cases of ZCN-induced movement disorders. Cases: Case one is a 64-year-old woman who presented with oro-lingual (OL) dyskinesia with dysesthesias and bilateral upper extremity kinetic tremor. Case two is a 43-year-old man with a 20-month history of ZCN treatment who developed OL dyskinesia with dysesthesias, involuntary left hand and neck movements, hallucinations, dysesthesias on his feet, and gait imbalance. Case three is a 70-year-old man with a 4-month history of ZCN use who developed OL dyskinesia with dysesthesias. Conclusions: Intrathecal treatment of pain with ZCN may be complicated by a drug-induced movement disorder where OL dyskinesia is characteristic. The movement disorder is likely to be dose related and reversible with ZCN discontinuation, but a chronic movement disorder is also possible.

Effectiveness and Safety of Intrathecal Ziconotide: Final Results of the Patient Registry of Intrathecal Ziconotide Management (PRIZM).

BACKGROUND AND OBJECTIVES: The Patient Registry of Intrathecal Ziconotide Management evaluated the long-term effectiveness and safety of intrathecal ziconotide. METHODS: The study was a prospective, multicenter observational study of intrathecal ziconotide in US clinical practice. Patients were adults with severe chronic pain that warranted intrathecal therapy. Ziconotide was initiated as the single agent in the pump; however, other intrathecal medications were permitted. The primary efficacy outcome was ≥30% reduction in numeric pain rating scale score from baseline at week 12. A secondary outcome was patient global impression of change. Adverse events were solicited at each visit. RESULTS: The registry enrolled 93 patients. Seventy-four and 28 patients completed 12 weeks and 18 months of treatment, respectively. In the overall patient population, 17.4% had ≥30% pain reduction from baseline at week 12, with a mean reduction in pain of 10.9%. At month 18, 38.5% of patients had ≥30% pain reduction from baseline, with a mean pain reduction of 24.7%. Patient-rated improvement was reported in 67% of patients at week 12 and 71% at month 18. Almost all patients experienced adverse events, the most common of which were nausea (25.8%), confusional state (22.6%), and dizziness (20.4%). CONCLUSIONS: Final study analyses showed that intrathecal ziconotide provided clinically meaningful pain relief in 17.4% and 38.5% of patients at week 12 and month 18, respectively. At these same time points, patient-rated improvement was reported in at least two-thirds of patients. The safety profile was consistent with that listed in the ziconotide prescribing information.

Ziconotide Monotherapy: A Systematic Review of Randomised Controlled Trials.

INTRODUCTION: Chronic neuropathic pain is difficult to treat and is often refractory to most modalities of treatment. Ziconotide is a novel, potent, non-opioid, calcium channel blocking agent which has been shown in clinical trials to be effective in treating chronic neuropathic pain. METHODS: EMBASE, MEDLINE, CINAHL Plus and Web of Science electronic databases were searched for English language studies. Reference sections of articles were examined for further papers and the manufacturer of ziconotide was contacted for further unpublished data. Three randomised controlled trials in ziconotide monotherapy were included and subjected to a random effects meta-analysis. RESULTS: All three studies used the similar main outcome measure (visual analogue scale of pain intensity; VASPI) and were therefore comparable. A Jadad score was performed for each paper. Frequent serious adverse events (SAEs) were observed which resulted in two of the studies revising the protocol. The metaanalysis revealed a pooled odds ratio (responders on ziconotide vs. placebo) of 2.77 (95% CI, 1.37 to 5.59). DISCUSSION: The results suggest that ziconotide is beneficial for pain reduction in chronic neuropathic pain. However, there remain some methodological issues that may call into question the validity of the results. It is evident that more work needs to be conducted to further validate the efficacy of ziconotide and to discover new areas of use.

Rationale for Prospective Assays of Intrathecal Mixtures Including Morphine, Ropivacaine and Ziconotide: Prevention of Adverse Events and Feasibility in Clinical Practice.

BACKGROUND: Use of intrathecal admixtures is widespread, but compounding these is sometimes challenging and may result in errors and complications causing super-potency or sub potency adverse events in patients or malfunctions in the pump itself. OBJECTIVE: The purpose of this study is to evaluate the accuracy of compounding of intrathecal admixtures through a prospective, systematic quantitative analysis of each component of the mixture before delivery to patients. STUDY DESIGN: Observational follow up prospective study of intrathecal mixtures components concentrations before refills. SETTINGS: Assays were performed on all intrathecal admixtures produced by the ICO-Paul Papin compounding pharmacy between January 2013 and October 2014 using Ultra High Performance Liquid Chromatography (U.H.P.L.C.). In addition, pH levels of admixtures have been measured since June 2014. When measured concentrations were 15% above or below the required concentrations, the mixture was excluded and compounded again. RESULTS: 1729 mixtures were analyzed. Mean deviation from theoretical values was -1.17% ± 0.28% for morphine, -0.95% ± 1.07% for ropivacaine, and 4.82% ± 0.6% for ziconotide. Exclusion rates were 8.33% overall, but fell from 11.67% in 2013 to 4.97% in 2014. Most exclusions were caused by inaccuracy in the dose of ziconotide. Average mixture pH of the 603 tested admixtures was 4.83 ± 0.6%. LIMITATIONS: This study is monocentric and limitations include also its non-randomized nature with no clinical comparison of the rate of adverse events with a refill process without control of each component concentrations. CONCLUSION: Prospective assays provide benefits in ensuring accuracy of intrathecal mixture compounding and in preventing overdosing or sub dosing, most notably concerning Ziconotide.

The Relationship Between the Mechanisms of Action and Safety Profiles of Intrathecal Morphine and Ziconotide: A Review of the Literature.

OBJECTIVE: To better characterize safety profiles associated with the intrathecal (IT) administration of morphine and ziconotide and discuss how they relate to mechanisms of action. METHODS: Published data were evaluated to identify potential relationships between safety profiles of IT morphine and IT ziconotide and their mechanisms of action. RESULTS: Potentially severe and clinically relevant adverse events (AEs) associated with IT morphine include respiratory depression, tolerance, and granuloma formulation, whereas IT ziconotide is associated with neuropsychiatric AEs, such as cognitive impairment, hallucinations, and changes in mood or consciousness, particularly with high doses and rapid titration. AEs associated with these IT therapies may result from spread of the medication out of the IT space into areas of the central and peripheral nervous systems and systemic circulation. AEs that occur usually can be managed and, in some cases, prevented. To mitigate risk, patients' histories should be reviewed to identify potential complicating factors (e.g., obesity or other risk factors for respiratory dysfunction in patients receiving IT morphine; a history of psychosis in patients receiving IT ziconotide). Also, treatment should be initiated at a low dose, titrated slowly, and patients should be closely monitored during treatment. CONCLUSIONS: IT morphine and IT ziconotide are approved by the US Food and Drug Administration for patients who do not respond to less invasive treatments, but the safety profiles of each may make them more or less appropriate for certain patient populations.

Ziconotide Combination Intrathecal Therapy for Noncancer Pain Is Limited Secondary to Delayed Adverse Effects: A Case Series With a 24-Month Follow-Up.

OBJECTIVES: The efficacy and safety of ziconotide as a single agent has been evaluated in few short-term clinical trials and open-label studies. Ziconotide use is challenging given its adverse effect (AE) profile. The objective of this study is to describe the long-term efficacy and AEs of ziconotide used as an adjunct to other intrathecal (IT) agents in chronic noncancer pain patients. MATERIALS AND METHODS: A case series of chronic noncancer pain patients who had suboptimal pain control from IT therapy. Ziconotide was introduced in the IT infusion mixture after a successful ziconotide trial. Pain scores, IT doses, as well as AEs were recorded and analyzed from trial to initial ziconotide infusion and up to 24 months. RESULTS: Fifteen patients underwent ziconotide trials. Four subjects failed the trial, and 11 proceeded to continuous ziconotide treatment. Seven out of 11 patients experienced AEs resulting in ziconotide discontinuation. Two of the seven subjects who required discontinuation of ziconotide had improved pain. Four subjects were able to continue IT ziconotide through 24 months. CONCLUSIONS: A high incidence of AEs limits the usefulness of IT ziconotide as adjunct therapy. Our results are limited by the size of our patient population; however, they represent a long follow-up period, which is limited in most current publications on this IT peptide. While ziconotide is a needed IT agent, more studies are necessary to better understand the factors that would improve the treatment to trial ratio as well as the long-term efficacy of IT ziconotide treatment.

Intrathecal Pharmacology Update: Novel Dosing Strategy for Intrathecal Monotherapy Ziconotide on Efficacy and Sustainability.

INTRODUCTION: Intrathecal drug delivery is a well-defined strategy to treat malignant and nonmalignant pain. Ziconotide is a well-studied intrathecal medicine option that has many attractive qualities, as it is non-granulomagenic, overdose or underdose is not associated with cardiopulmonary compromise or death, and is a non-opoid analgesic. However, it has had slow adoption into pain care algorithms because it has been historically plagued with the connotation of having a narrow therapeutic window and a low sustainability rate. We introduce a novel dosing strategy to improve patient outcomes and sustainability. METHODS: Patients were identified as being an intrathecal candidate and trialed with ziconotide based on the current standard of care. Patient demographics, diagnosis, previous treatment failures, and pre-implant visual analog scale (VAS) scores were recorded. Once the trial was deemed successful, based on the dual bolusing strategy, the patient underwent device implantation. Consecutive patients were prospectively followed. Ziconotide was then initiated with a flex dosing strategy, weighted during nocturnal dosing. Outcome endpoints included: reduction in VAS, side effects, durability of therapy, and systemic opioid use prior to implant and at last visit were noted (calculated to daily morphine equivalents). Primary endpoint was tolerability of ziconotide at three months following new dosing strategy. No industry support or funding was obtained for this project. RESULTS: All enrolled patients met the endpoint of the study of tolerability of ziconotide at three months. Numbers declined to 75% of patients at four months, and 70% of patients at six months. The discontinuing side-effects were most commonly urinary retention and visual hallucinations. There were no serious adverse events and no unresolved complications reported. Numerical rating scale (NRS) decreased on average from 9.06 to 1.8. Opioid reduction in morphine equivalents averaged 91.5% DISCUSSION: The efficacy and tolerability of monotherapy ziconotide may be improved by using a weighted bolus flex dosing strategy as compared with slow continuous infusions. CONCLUSION: We present a novel strategy to deliver ziconotide using a unique continuous infusion flex dosing strategy. Further randomized, prospective, higher-powered studies are needed to critically evaluate the conclusions suggested by this limited prospective case series.

Acute rhabdomyolysis in a patient with long-term exposure to intrathecal ziconotide: a case report.

INTRODUCTION: Ziconotide is an intrathecally administered nonopioid analgesic for the treatment of severe chronic pain. Previous reports have noted rhabdomyolysis in patients receiving ziconotide during the initial single-shot trial or due to concurrent medical problems. We present a case of an acute rhabdomyolysis following an intrathecal bolus injection of ziconotide on a patient who had long-term exposure to the drug. CASE REPORT: The patient suffered from chronic neuropathic pain with diagnosis of failed back surgery syndrome and received intrathecal ziconotide for 2 years. Moderate side effects resulting from dose escalation led to a discontinuation of the drug. The pump medication was changed to morphine, which failed to provide adequate analgesia even with dose titration. A single intrathecal bolus of ziconotide, as an adjunctive therapy, resulted in good pain control. Two months later, the patient received a second ziconotide injection. Sixteen hours after the injection, she presented to local emergency center with nausea, vomiting, diarrhea, and myalgia. She had significantly increased CK levels and was admitted for intravenous hydration and close observation. Her serum CK level peaked at 4940 IU/L. The patient was discharged on hospital day 3 with a CK level of 808 IU/L. Her symptoms resolved without renal impairment. DISCUSSION: The clinical scenario described is a case of acute rhabdomyolysis from an intrathecal bolus injection of ziconotide in a patient with prior long-term exposure to the drug. The decrease in CK levels coincided well with the average half-life of ziconotide; however, the rhabdomyolysis may have been potentiated by hypokalemia.

Ziconotide-induced psychosis: a case report.

Ziconotide is used intrathecally in the management of severe chronic pain that contains a warning against neuropsychiatric adverse events. The definition of psychiatric events is broad and management strategies are vague. This case report describes a 49-year-old female who was admitted to the acute psychiatric unit to address auditory hallucinations and paranoid ideation persisting for 3 weeks. Approximately 3 months ago, an intrathecal pump with ziconotide was implanted to treat pain. Upon hospital admission, the pump was infusing at a rate of 4.9 mcg/24 hours. Because the drug could not be immediately discontinued, risperidone 0.5 mg nightly was initiated and subsequently, the pump was drained of ziconotide, rinsed, and refilled with normal saline. The patient reported no hallucinations or apparent delusions several hours later and was eventually discharged with resolution of psychotic symptoms and continuation of risperidone for 10 days. Despite the identification of neuropsychiatric effects, limited information is available to characterize the presentation and guide specific management aside from recommendations to discontinue the infusion and possible use of psychotropic medications or necessity for hospitalization. This case report characterizes one presentation of hallucinations and paranoia associated with ziconotide intrathecal infusion. Clinicians should be aware of the management strategies to mediate these adverse effects, including expected time to adverse effect resolution, removal of ziconotide from the pump, and role for short-term use of antipsychotics.

Dyskinesia caused by ziconotide-baclofen combination in an adolescent affected by cerebral palsy.

OBJECTIVE: To report on the first case of ziconotide-induced dyskinesia. Ziconotide, a synthetic peptide analogue of the ω-conotoxin MVIIA that blocks selectively N-type voltage-sensitive calcium channels, has been used in intrathecal administration for 30 years. Ziconotide is a drug of choice for chronic pain because of its efficacy and flexibility because it can substitute or complement other intrathecal therapies including morphine or baclofen. Whereas substantial information is available regarding its efficacy, systematic data regarding the safety of ziconotide remain scant. The adverse reactions to ziconotide described so far regard only the coordination and execution of intentional movements. CASE REPORT: A 15-year-old male patient developed dyskinesia affecting the head and upper limbs 2 days after administration of ziconotide as an add-on therapy to an established regimen of treatment with baclofen. The strict temporal relationship between ziconotide administration and dyskinesia, together with the absence of any other clinical alteration, led to the hypothesis of a possible adverse drug reaction. Ziconotide was thus withdrawn, and the symptoms disappeared within 2 days. CONCLUSIONS: An analysis of the signaling pathways of baclofen and ziconotide revealed a possible drug interaction that allowed ziconotide to trigger dyskinesia.

Ziconotide.

Questions from patients about pain conditions and analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self-advocates. The topics addressed in this issue are ziconotide, a novel approach to pain management that is derived from a snail toxin, its uses and possible side effects.

Intrathecal ziconotide: a review of its use in patients with chronic pain refractory to other systemic or intrathecal analgesics.

Ziconotide (Prialt(®)) is a synthetic conopeptide analgesic that acts by selectively antagonizing N-type voltage-gated calcium channels. Intrathecal ziconotide is the only non-opioid intrathecal analgesic that is FDA-approved for use in patients with treatment-refractory, chronic pain. The efficacy of intrathecal ziconotide was demonstrated in randomized, double-blind, placebo-controlled trials in patients with treatment-refractory noncancer-related pain or cancer- or AIDS-related pain. Across trials, ziconotide recipients had significantly greater reductions in pain intensity during ziconotide treatment than those receiving placebo (primary endpoint). At the end of the titration period, approximately one-sixth to one-third of patients with noncancer chronic pain and one-half with cancer- or AIDS-related pain who received ziconotide reached a pain response threshold (≥30 % reduction in the pain intensity score). In ziconotide responders, analgesic effects were enduring, with some patients continuing treatment over extended periods. Across trials, the chief tolerability concerns in ziconotide recipients during the titration phase and during extended treatment were related to CNS adverse events. These were mostly of mild to moderate intensity, although serious adverse events were commonly attributed to ziconotide treatment, especially in trials with rapid ziconotide titration and that permitted higher dosages. In general, clinically important non-CNS adverse events were infrequent, and during the ziconotide titration phase, relatively few patients discontinued treatment because of adverse events. Ongoing research will assess various strategies for selecting patients for ziconotide treatment and for enhancing its efficacy and tolerability. At the present time, intrathecal ziconotide provides a treatment option for patients with severe, unremitting pain who have failed to respond to other intensive analgesic regimens.

Spider peptide Phα1ß induces analgesic effect in a model of cancer pain.

The marine snail peptide ziconotide (ω-conotoxin MVIIA) is used as an analgesic in cancer patients refractory to opioids, but may induce severe adverse effects. Animal venoms represent a rich source of novel drugs, so we investigated the analgesic effects and the side-effects of spider peptide Phα1ß in a model of cancer pain in mice with or without tolerance to morphine analgesia. Cancer pain was induced by the inoculation of melanoma B16-F10 cells into the hind paw of C57BL/6 mice. After 14 days, painful hypersensitivity was detected and Phα1ß or ω-conotoxin MVIIA (10-100 pmol/site) was intrathecally injected to evaluate the development of antinociception and side-effects in control and morphine-tolerant mice. The treatment with Phα1ß or ω-conotoxin MVIIA fully reversed cancer-related painful hypersensitivity, with long-lasting results, at effective doses 50% of 48 (32-72) or 33 (21-53) pmol/site, respectively. Phα1ß produced only mild adverse effects, whereas ω-conotoxin MVIIA induced dose-related side-effects in mice at analgesic doses (estimated toxic dose 50% of 30 pmol/site). In addition, we observed that Phα1ß was capable of controlling cancer-related pain even in mice tolerant to morphine antinociception (100% of inhibition) and was able to partially restore morphine analgesia in such animals (56 ± 5% of inhibition). In this study, Phα1ß was as efficacious as ω-conotoxin MVIIA in inducing analgesia in a model of cancer pain without producing severe adverse effects or losing efficacy in opioid-tolerant mice, indicating that Phα1ß has a good profile for the treatment of cancer pain in patients.

Ziconotide: a clinical update and pharmacologic review.

INTRODUCTION: Ziconotide is an N-type calcium channel antagonist to treat chronic pain that is delivered intrathecally. It is the only intrathecal, FDA-approved, non-opioid analgesic and is recommended as first-line therapy. Despite these advantages, a small therapeutic window limits ziconotide's clinical utility, with adverse event (AE) challenges that include, but are not limited to, dizziness, nausea, and somulence. AREAS COVERED: Pharmacokinetics, pharmacodynamics, efficacy, safety, trialing, and chronic infusion after searching EMBASE, PubMed, and Cochrane Database of Systemic Reviews were used to search published literature from 1966 to January 1, 2013 to identify studies related to the intrathecal delivery of ziconotide. EXPERT OPINION: Ziconotide is a safe and effective strategy to treat chronic pain, although limitations remain, including a small therapeutic window. Low starting doses and slow incremental increases and long titration intervals may improve tolerability. AEs may be mitigated by also employing combination therapy, although further study is needed. Concomitant use of ziconotide and morphine is an option when considering use of FDA-labeled intrathecal drugs in those resistant to monotherapy.

Omega-conotoxins as experimental tools and therapeutics in pain management.

Neuropathic pain afflicts a large percentage of the global population. This form of chronic, intractable pain arises when the peripheral or central nervous systems are damaged, either directly by lesion or indirectly through disease. The comorbidity of neuropathic pain with other diseases, including diabetes, cancer, and AIDS, contributes to a complex pathogenesis and symptom profile. Because most patients present with neuropathic pain refractory to current first-line therapeutics, pharmaceuticals with greater efficacy in pain management are highly desired. In this review we discuss the growing application of ω-conotoxins, small peptides isolated from Conus species, in the management of neuropathic pain. These toxins are synthesized by predatory cone snails as a component of paralytic venoms. The potency and selectivity with which ω-conotoxins inhibit their molecular targets, voltage-gated Ca2+ channels, is advantageous in the treatment of neuropathic pain states, in which Ca2+ channel activity is characteristically aberrant. Although ω-conotoxins demonstrate analgesic efficacy in animal models of neuropathic pain and in human clinical trials, there remains a critical need to improve the convenience of peptide drug delivery methods, and reduce the number and severity of adverse effects associated with ω-conotoxin-based therapies.

Bolus intrathecal injection of ziconotide (Prialt®) to evaluate the option of continuous administration via an implanted intrathecal drug delivery (ITDD) system: a pilot study.

OBJECTIVES: This study evaluated efficacy and safety of bolus doses of ziconotide (Prialt®, Eisai Limited, Hertfordshire, UK) to assess the option of continuous administration of this drug via an implanted intrathecal drug delivery system. MATERIALS AND METHODS: Twenty adults with severe chronic pain who were under consideration for intrathecal (IT) therapy were enrolled in this open label, nonrandomized, pilot study. Informed consent was obtained. Demographics, medical/pain history, pain scores, and concomitant medications were recorded. A physical examination was performed. Creatine kinase was measured. Initial visual analog scale (VAS), blood pressure, heart rate, and respiratory rate were recorded. All patients received an initial bolus dose of 2.5 mcg ziconotide; the dose in the subsequent visits was modified according to response. Subsequent doses were 2.5 mcg, 1.2 mcg, or 3.75 mcg as per protocol. A good response (≥30% reduction in baseline pain VAS) with no side-effects on two occasions was considered a successful trial. Data were analyzed using a generalized estimating equations model, with pain VAS as the outcome and time (seven time points; preinjection and one to six hours postinjection) as the predictor. RESULTS: Generalized estimating equations analysis of summary measures showed a mean reduction of pain VAS of approximately 25% at the group level; of 11 responders, seven underwent pump implantation procedure, two withdrew because of adverse effects, one refused an implant, and one could not have an implant (lack of funding from the Primary Care Trust). CONCLUSIONS: Our data demonstrated that mean VAS was reduced by approximately 25% at the group level after IT ziconotide bolus. Treatment efficacy did not vary with sex, center, age, or pain etiology. Ziconotide bolus was generally well tolerated. Larger studies are needed to determine if bolus dosing with ziconotide is a good predictor of response to continuous IT ziconotide via an intrathecal drug delivery system.